The Fifth Affiliated Hospital, Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, the School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, PR China.
Biomaterials Research Center, School of Biomedical Engineering, Southern Medical University, Guangzhou, 510515, PR China.
Biomaterials. 2024 Jul;308:122568. doi: 10.1016/j.biomaterials.2024.122568. Epub 2024 Apr 12.
The crosstalk between breast cancer cells and tumor associated macrophages (TAMs) greatly contributes to tumor progression and immunosuppression. In this work, cat eye syndrome chromosome region candidate 2 (CECR2) is identified to overexpress in breast cancer patients, which can recognize v-rel avian reticuloendotheliosis viral oncogene homolog A (RelA) and activate nuclear factor κB (NF-κB) to release colony stimulating factor-1 (CSF-1). Pharmacological inhibition of CECR2 by the bromodomain competitor (Bromosporine, Bro) can downregulate CSF-1 to inhibit M2 type TAMs. To amplify the immunotherapeutic effect, a chimeric peptide-based and optical controlled CECR2 competitor (designated as N-PB) is constructed to enhance the nuclear targeted delivery of Bro and initiate an immunogenic cell death (ICD). In vivo results indicate a favorable breast cancer targeting ability and primary tumor suppression effect of N-PB under optical irradiation. Importantly, N-PB downregulates CSF-1 by competitive inhibition of CECR2 and NF-κB(RelA) interactions, thus inhibiting immunosuppressive M2-like TAMs while improving the antitumorigenic M1-like phenotype. Ultimately, the systemic anti-tumor immunity is activated to suppress the metastatic breast cancer in an optical controlled manner. This study provides a promising therapeutic target and reliable strategy for metastatic breast cancer treatment by interrupting immunosuppressive crosstalk between tumor cells and macrophages.
乳腺癌细胞与肿瘤相关巨噬细胞（TAMs）之间的串扰极大地促进了肿瘤的进展和免疫抑制。在这项工作中，鉴定出猫眼综合征染色体区域候选基因 2（CECR2）在乳腺癌患者中过表达，它可以识别 v-rel 禽网状内皮增生病病毒癌基因同源物 A（RelA）并激活核因子 κB（NF-κB）释放集落刺激因子-1（CSF-1）。通过溴结构域竞争物（Bromosporine，Bro）抑制 CECR2 的药理作用可以下调 CSF-1 以抑制 M2 型 TAMs。为了放大免疫治疗效果，构建了基于嵌合肽和光控 CECR2 竞争物（命名为 N-PB），以增强 Bro 的核靶向递送并引发免疫原性细胞死亡（ICD）。体内结果表明，在光学照射下，N-PB 具有良好的乳腺癌靶向能力和原代肿瘤抑制作用。重要的是，N-PB 通过竞争性抑制 CECR2 和 NF-κB（RelA）相互作用下调 CSF-1，从而抑制免疫抑制性 M2 样 TAMs，同时改善抗肿瘤 M1 样表型。最终，通过光控方式激活全身抗肿瘤免疫来抑制转移性乳腺癌。这项研究为通过阻断肿瘤细胞和巨噬细胞之间的免疫抑制串扰治疗转移性乳腺癌提供了一个有前途的治疗靶点和可靠策略。
